tbuckley/cabot-search huggingface dataset:
Abstract 15360: Characteristics and In-Hospital Outcomes of Patients Undergoing Pulmonary Vein Isolation With and Without Adjunctive Lesions: Insights From the Ncdr Afib Ablation Registry
Authors: Douglas J Darden, Omar M Aldaas, Chengan Du, Gregory K Feld, Krishna Pothineni, Rakesh Gopinathannair, Dhanunjaya R Lakkireddy, Jeptha P Curtis, James V Freeman, Joseph Akar, Jonathan C Hsu
Journal: Circulation (2022)

Introduction: The optimal ablation strategy beyond pulmonary vein isolation (PVI) for atrial fibrillation (AFib) is undefined. No prior study has been adequately powered to evaluate real-world safety outcomes in those receiving adjunctive (adj) ablation lesions. We sought to evaluate characteristics and in-hospital complications among patients undergoing AFib ablation with PVI with and without adj lesions. Hypothesis: PVI + adj will be more common in those with persistent AF (persAF) and be associated with adverse events. Methods: Patients enrolled in the National Cardiovascular Data Registry AFib Ablation Registry undergoing first-time ablation between 2016 and 2020 were stratified into paroxysmal (PAF) and persAF, and separated into PVI only, PVI+cavotricuspid isthmus (CTI) ablation alone, PVI+adj (SVC isolation, coronary sinus, vein of Marshall, atypical atrial flutter lines, other). In-hospital outcomes were compared using multivariable logistic regression. Results: A total of 50,937 patients were included. Among PAF, as compared to PVI only, both PVI+CTI and PVI+adj were associated with prolonged hospitalization after adjustment, while there were no differences in complications. In the persAF cohort, as compared to PVI only, PVI+adj was associated with a higher risk of any complication and major complication, while no differences were observed in PVI+CTI (Table). In-hospital death was rare with no differences across groups. Conclusion: Adjunctive lesions are commonly performed in real-world practice in both PAF and persAF with varied strategies. Among PAF, additional lesions were associated with prolonged hospitalization, although not complications. Among persAF, PVI+adj, but not PVI+CTI, was associated with a higher risk of complications. While additional CTI ablation may be considered safe in persAF, further efforts to determine optimal ablation strategies beyond PVI and mitigate risk are warranted.
Abstract 14588: A Large-Scale Genome-Wide Association Study of Angiographically Determined Burden of Coronary Atherosclerosis in a Genetically Diverse Population
Authors: Austin Hilliard, Daniela Zanetti, julie lynch, Scott M Damrauer, Yuk-lam Ho, Meg E Plomondon, Stephen Waldo, Kyong-Mi Chang, Philip S Tsao, Shoa L CLARKE, Themistocles L Assimes
Journal: Circulation (2022)

Introduction: Few large-scale genome wide association studies (GWAS) of angiographically derived burden of coronary atherosclerosis have been reported to date. The yield of this approach relative to case-control GWAS of coronary artery disease (CAD) remains unclear. Methods: We used the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program, a national quality and safety organization for invasive cardiac procedures, to conduct the largest ever GWAS of burden of coronary atherosclerosis involving participants of the Million Veteran Program (MVP). Obstructive disease of a native major vessel was defined as the presence of at least one obstruction &gt;50% of the luminal diameter, or a prior revascularization procedure, involving the main artery and/or its major branches. Non-obstructive disease was defined as one or more vessels having one or more obstructions of &gt;20% but none more than 50%. We classified an individual’s extent of disease as normal, non-obstructive, one vessel, two vessel, or three vessel / left main CAD. GWAS was performed stratified by racial/ethnic group using linear regression in REGENIE, with age, sex, and genetic principal components as covariates. Stratified results were then combined through meta-analysis using GWAMA. Results: The extent of disease was quantified in 49,213 non-Hispanic White, 11,326 non-Hispanic Black, and 4,058 Hispanic MVP participants, a majority of which were subjects with clinical CAD. Forty-three loci reached genome wide significance including 27 among Whites, four among Blacks at SORT1 , LPL , COL4A2 , and LDLR , two among Hispanics at CDKN2B-AS1 and NRG4 , and an additional 13 through meta-analysis of all three strata. Two loci, HHEX and NRG4 , have not been previously established as susceptibility loci CAD. Conclusions: Large-scale GWAS of burden of coronary atherosclerosis complements discovery efforts of case-control GWAS of CAD. Despite substantially smaller sample sizes, this quantitative approach recapitulated many established loci for CAD, uncovered novel loci, and identified several known susceptibility loci in admixed Black and Hispanic populations. The latter required a remarkably larger sample size to achieve through GWAS of clinically defined events alone.
Abstract 15700: ALK1-Mediated Smad1 Activation in a Myofibroblast Subset Protects the Infarcted Heart From Adverse Remodeling and Excessive Fibrosis
Authors: Anis Hanna, Nikolaos Frangogiannis
Journal: Circulation (2022)

Cardiac fibroblasts acquire inflammatory, proangiogenic, or matrix-synthetic phenotypes following MI and play a pivotal role in repair and remodeling of the infarcted heart. Members of the Transforming Growth Factor (TGF)β superfamily (including TGFβs and BMPs) are activated following MI and regulate fibroblast phenotype and cardiac fibrosis. Canonical TGFβ signaling is mediated through the receptor-activated Smads: TGF-βs activate Smad2/3, whereas BMPs predominantly stimulate Smad1/5 cascade. Smad3 signaling plays an important role in activation of infarct myofibroblasts; however, the role of the Smad1 pathway remains unknown. We hypothesized that fibroblast-specific actions of Smad1 regulate repair and remodeling in the infarcted myocardium. In a mouse model of non-reperfused infarction, Smad1 was activated in a subset of cardiac myofibroblasts not only by BMPs, but also by all three TGF-β isoforms. TGF-β activation of Smad1 was dependent on both ALK1 and ALK5 signaling. Analysis of single cell RNA-seq data suggested that ALK1 is a marker of a myofibroblast subset exhibiting anti-fibrotic properties. In order to examine the role of fibroblast Smad1 in vivo, we generated mice with myofibroblast-specific Smad1 loss (MFS1KO). Echocardiography showed that MFS1KO mice have accentuated systolic dysfunction and LV dilation 7-28 days after MI (p&lt;0.01, N=13-49) . Worse adverse remodeling in infarcted MFS1KO hearts was associated with scar expansion, higher myofibroblast density and accentuated fibrosis. Smad1 knockdown in cardiac fibroblasts increased mRNA levels of structural and matricellular genes while reducing matrix metalloproteinase synthesis. RNA-seq showed that Smad1 loss activates pathways involved in matrix regulation and collagen biosynthesis, and suggested that Smad1 may exert anti-fibrotic actions through inhibition of TGF-β/Smad3 axis, p53, and IL4/STAT6 pro-fibrotic cascades. In conclusion, Smad1 activation in a subset of anti-fibrotic infarct myofibroblasts restrains cardiac fibrosis and protects from adverse remodeling by inhibiting key pro-fibrotic pathways. These findings suggest that Smad1 activation in fibroblasts may be a promising strategy to restrain cardiac fibrosis in infarcted and failing hearts.
Abstract 14433: Rates of Serious Adverse Events During Home-Based Exercise in Lower Extremity Peripheral Artery Disease: Results From Three Randomized Clinical Trials
Authors: Pooja Nayak, Lu Tian, Lihui Zhao, Shujun Xu, Mary M McDermott
Journal: Circulation (2022)

Background: Home-based exercise is recommended by guidelines for people with lower extremity peripheral artery disease (PAD) to improve walking performance. This post-hoc analysis of three randomized clinical trials studied the association of home-based exercise, compared to control, on rates of serious adverse events in people with PAD. Methods Data were combined from three randomized clinical trials that compared home-based walking exercise to a control group that did not exercise. In all three trials, people with an abnormal baseline exercise stress test were excluded. Participants randomized to home-based exercise worked with a coach, who used behavioral methods to help them adhere to home-based walking exercise, consisting of walking for exercise five times per week for up to 50 minutes/session. The control groups received educational sessions instead of exercise. Participants were questioned each month about occurrence of serious adverse events, defined as hospitalizations, deaths, or events causing persistent disability. Results 651 people with PAD from three randomized trials were included (mean age 70, 49% women, 53% Black). People randomized to exercise had higher rates of cardiovascular events than control (Table). Among those randomized to exercise, people with history of myocardial infarction (p=0.0002), angina (p=0.0004), stroke (p=0.03), pulmonary disease (p=0.02), and poorer baseline six-minute walk distance (280.29 vs 338.15 meters, p=0.0002) had higher rates of cardiovascular events. Conclusion In these post-hoc analyses, people with PAD randomized to a home-based walking exercise intervention had higher rates of cardiovascular events, compared to a control group during the trial. Further study is needed to determine whether this association represents a causal effect. People with PAD who have lower six-minute walk distance or a history of cardiovascular disease may require closer monitoring during a home-based exercise program.
Prevalence of mental illness in a community nursing home
Authors: Barry W Rovner, Stephanie Kafonek, Laura Filipp, Mary Jane Lucas, Marshal F. Folstein
Journal: American Journal of Psychiatry (1986)

A research psychiatrist using a standardized interview found that 94% of a random sample of residents at a large, intermediate-care nursing home had mental disorders according to DSM-III criteria. Primary degenerative dementia and multi-infarct dementia were the most common diagnoses. In addition, the majority of demented patients also had noncognitive symptoms such as delusions and hallucinations, and these residents were significantly more likely to have an associated behavioral disorder than were residents without delusions or hallucinations. Replications of these results would point out the need for major revisions in the funding and delivery of psychiatric care for nursing home residents.
Abstract 15362: Checkpoint Kinase 1-Associated Senp2 S344 Phosphorylation Under Laminar Flow Attenuates Endothelial-Mesenchymal Transition and Atherogenesis
Authors: Minh T Nguyen, Masaki Imanishi, Shengyu Li, Kyung Ae Ko, Priyanka Banerjee, Loka reddy Velatooru, Elena McBeath, Keigi Fujiwara, Sivareddy Kotla, Khanh Chau, Rei Abe, mae k borchardt, Edward T Yeh, John P Cooke, Guangyu Wang, Junichi Abe, Nhat Tu T Le
Journal: Circulation (2022)

Aims: To investigate the role of Checkpoint Kinase 1 (CHK1)-associated SENP2 S344 phosphorylation in laminar flow (LF)-regulated Endothelial-Mesenchymal Transition (EndMT) inhibition and the underlying mechanisms. Methods: We generated deSUMOylation enzyme sentrin-specific isopeptidase 2 (SENP2) S343A (equivalent to human SENP2 S344) knock-in (KI) and endothelial cell (EC)-specific SENP2 knock-out (SENP2 EKO) mice to detect EC activation, EndMT, and atherogenesis in vitro and in vivo . We also performed next-generation RNA sequencing (RNA-seq) analysis in ECs derived from these mice. Results: LF, but not disturbed flow (DF), triggered SENP2 S344 phosphorylation through CHK1. The decreased ERK5- and p53-SUMOylation by LF was abolished in ECs derived from SENP2 S343A KI mice. Both EC apoptosis and VCAM-1 expression were upregulated in SENP2 S344A KI mice. The increased atherogenesis in SENP2 S344A KI was regulated by vascular, but not hematopoietic, cells based on bone marrow transplantation (BMT) study. CHK1 expression was decreased by ionizing radiation (IR), leading to an enhanced ERK5- and p53-SUMOylation as well as EC inflammation. RNA-seq analysis revealed the involvement of SENP2 S344 phosphorylation in changes of fibrotic phenotypes and EndMT-related genes. Further, SENP2 S344A point mutation prevented LF-regulated TGFbR1 SUMOylation inhibition in vitro, as well as hypercholesterolemia-induced EndMT in vivo. Discussions: These data revealed the unique role of CHK1-associated SENP2 S344 phosphorylation in not only LF-regulated EndMT inhibition but also IR-associated EndMT activation and the subsequent atherogenesis. Maintaining CHK1-associated SENP2 S344 phosphorylation can be an ideal approach to mitigate EndMT, which is important in tumor radio-resistance as well as IR-associated cardiovascular disease.
Abstract 14664: Heart Failure as the Cancer for the Heart: The Prognostic Role of the New HLM Score
Authors: Paolo Severino, Andrea D'Amato, Marco Valerio Mariani, Silvia Prosperi, Danilo Alunni Fegatelli, Lucia Ilaria Birtolo, Bettina Costi, Danilo Angotti, Enrico Cerrato, Carlo Lavalle, Viviana Maestrini, Carmine Pizzi, Alberto Foà, annarita vestri, Alberto Palazzuoli, Paul J. Mather, Paul N. Casale, Massimo Mancone, Francesco Fedele
Journal: Circulation (2022)

Introduction: The multiorgan involvement of heart failure is similar to the spread observed in cancer. We proposed a new score system, named HLM, analogous to TNM classification used in oncology. HLM refers to (i) H: heart damage, instead of “T” for tumor; (ii) L: lung involvement, instead of “N” for lymph nodes; (iii) M: involvement of peripheral organs, instead of “M” for metastasis. Hypothesis: to compare HLM score to NYHA class, ACC/AHA stages and HF classification by left ventricular ejection fraction (LVEF), to assess the most accurate prognostic tool for HF patients. Methods: We performed a multicentric, observational, prospective study of consecutive patients admitted for HF, or at risk for HF. All parameters for heart, lungs and organs’ function were collected. HLM score, made up of 4 stages of severity, was built starting from HLM classification. Each patient was classified according to HLM, NYHA, ACC/AHA stages and LVEF. The primary composite endpoint was all-cause death and rehospitalization due to HF; patients were followed up for 12 months. Results: We enrolled 1720 patients who completed the 12-months follow-up. As showed by Kaplan Meier curves, HLM was the most accurate score to predict primary endpoint at 12 months. The area under the ROC curve (AUC) was greater for HLM score than NYHA, ACC/AHA stages and LVEF classification, regarding the composite endpoint (HLM=0.645; NYHA=0.580; ACC/AHA=0.572; LVEF=0.572). HLM score related AUC showed statistically significant differences compared to LVEF (p=0.002), ACC/AHA (p=0.002) and NYHA (p=0.009). Conclusions: HLM score has a greater prognostic power compared to other nosologies, in terms of the composite endpoint of all-cause death and rehospitalization, at 12 months follow up.
Abstract 14636: The Effects of Celecoxib on Endothelial Function in Healthy Volunteers; A Double Blind, Placebo Controlled Randomised Trial
Authors: Ricky Vaja, Plinio Ferreira, Peter Collins, Matthew Rickman, Prakash P Punjabi, Nicholas Kirkby, Jane Mitchell
Journal: Circulation (2022)

Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs), which work by blocking cyclooxygenase (COX)-2 can increase cardiovascular risk by up to 30% after 2 weeks of use and in animal models augments thrombosis. However, the effect of NSAIDs and loss of COX-2 on endothelial function and blood flow remains incompletely understood. A plausible explanation is inhibition of COX-2 affects endothelial function by inhibiting prostacyclin and/or reducing endothelial nitric oxide synthase (eNOS) activity/expression. We hypothesised that COX-2 inhibition with celecoxib will impact on endothelial function. Methods: Healthy male volunteers aged between 18 to 40 were randomised 1:1 to receive either celecoxib (200 mg twice daily) or matching placebo for 7 days. The primary outcome was change (Δ) in endothelial function assessed using the EndoPAT device. Participants were given a home blood pressure machine and diary as a secondary outcome measure. Participants and outcome assessors were blinded to the intervention. Results: Between June 2021 and January 2022, 44 participants were randomised of which 40 participants completed the study (20 allocated to each arm) and were included in the final analysis. Baseline characteristics were similar between the groups. Compared to placebo, there was a significant increase in augmentation index (AI) following celecoxib use: Δ 6.2; (95% CI 0.05 to 12.4) p:0.048. There was no difference in log reactive hyperaemia index (LnRHI): Δ -0.092; (95% CI -0.31 to 0.12) p:0.39, systolic blood pressure: Δ -3.5; (95% CI -9.9 to 3) p:0.28, or diastolic blood pressure: Δ 4.7; (95% CI -1.8 to 11.1) p:0.15 (Figure) . Conclusion: In healthy male volunteers, 7 days of treatment with celecoxib significantly increased augmentation index which is a surrogate for vascular stiffness and an independent predictor of cardiovascular risk. Further clinical and mechanistic studies are required to elucidate how COX-2 inhibition impacts on augmentation index.
Abstract 15907: Patch Material Does Impact Reintervention After Aortic Arch Reconstruction: Single Center Experience
Authors: Shwetabh Tarun, Carlos Diaz-Castrillon, MELITA VIEGAS, Mario Castro, Luciana Da Fonseca Da Silva, Victor O Morell
Journal: Circulation (2022)

Objective: to evaluate reintervention rates after primary aortic arch reconstruction according to patch material. Methods: Patients undergoing primary surgical repair from October 2004 to December 2021 were identified. Univentricular physiology anatomies were excluded. Comparative analysis was performed between Homograft (81%), and Bovine pericardium (19%). The primary outcome was surgical or catheter-based reintervention. Kaplan-Meier function and Cox-regression analysis were used. Results: we included 160 patients with a median age and weight of 14 days (IQR 7-53) and 3.3 kg (IQR 2.9 - 4.2). The median follow-up time was 6.4 years (IQR 2.8 - 10.4). The clinical breakdown was Hypoplastic Aortic Arch/Aortic Coarctation in 89% (n=142) and Interrupted Aortic Arches in 10% (n= 17) (Table 1). Overall, 25% patients (n= 40) underwent a reintervention; 80% (n= 32) were balloon dilation angioplasties. After 1-, 5-, and 10-years post op, 78%, 74%, 72% of patients survived without reintervention, respectively. No differences were observed in the cumulative hazard between homograft and Bovine pericardium patch repairs (Figure 1). Multivariable cox regression showed an increased hazard for reintervention for bovine pericardium patches (HR 2.9, 95% CI 1.1 - 8.0) after controlling for age, weight, diagnosis, aortic arch, and aortic isthmus Z-Scores. Conclusion: Intermediate term outcomes after aortic arch reconstruction are favorable in a single center. Patch material is likely to be an important determinant for the risk of early restenosis requiring reintervention after aortic arch reconstruction.
Abstract 14691: Sex Differences in the Prognostic Value of N-Terminal Brain Natriuretic Peptide in Pulmonary Arterial Hypertension
Authors: Jessie Van Wezenbeek, Aida Llucia-Valldeperas, rowan Smal, Fjodor T Bekedam, Anton Vonk Noordegraaf, Marie Jose Goumans, Harm J Bogaard, Frances S De Man
Journal: Circulation (2022)

Introduction: Pulmonary arterial hypertension (PAH) causes right heart failure (HF) and mainly affects females, but males have worse survival. Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP), along with N-terminal BNP (NTproBNP), are secreted from cardiomyocytes upon stretch and are important biomarkers in HF. Sex differences are observed in NTproBNP levels and prognostic value in left HF, but unknown in right HF. The aim was to assess sex differences in NTproBNP levels and prognostic value in PAH from a translational perspective. Methods: We screened patients with baseline NTproBNP measurements and right heart catheterization between 2002 and 2020. Induced pluripotent stem cells (iPSCs) from 1 male and 1 female PAH-patients were differentiated into cardiomyocytes (iPSC-CMs), and stretched for 24h at 1Hz and 10% on the Flexcell FX-6000 system (N=2). Gene expression analyses were performed on static and stretched samples. Results: 266 patients (N=106 male, N=166 female) were included. Median baseline NTproBNP levels were similar in male and female patients (1118 vs 832 ng/ml, P=0.58). We risk stratified patients on NTproBNP according to the guidelines and assessed differences in 1-year survival. In males highest 1-year mortality was observed in low and low-intermediate risk groups (16,4% and 7.7%, respectively) vs females (4.7% and 4.2%, respectively) (Figure1 A,B). Preliminary results indicate ~2x higher BNP mRNA expressions on male vs female patients (0.80 vs 0.37, N=3 male and N=3 female, P=0.018), after mechanical stretch (Figure1 C). Conclusions: Although no sex differences were observed in NTproBNP plasma levels, it had different prognostic value in male and female patients. Furthermore, in vitro male iPSC-CMs had higher BNP levels after stretch compared to female iPSC-CMs.
Abstract 15331: Epigenetic Interaction of Grk4 and Slc4a5 Variants Regulates Gene Transcription and Blood Pressure
Authors: Daniel Yaqub, Shaun C Moore, Jacob Polzin, Laureano D Asico, hanna haile, Ines Armando, Pedro A Jose
Journal: Circulation (2022)

Salt sensitive hypertension is associated with variants of G protein-coupled receptor kinase 4γ (GRK4), as well as with activating variants of the solute carrier family 4 member 5 (rs7571842 and rs10177833; SLC4a5), which encodes the sodium bicarbonate transporter 2 (NBCe2). We tested the hypothesis that the effect of the R65L variant (rs2960306) of GRK4 (GRK4γ 65L) on salt-sensitivity involves a gene-gene interaction with SLC4a5 variants. We found that the renal expression of SLC4a5 is increased in salt sensitive transgenic mice expressing GRK4γ 65L and is higher (50%; n=4; P&lt;0.02) than that in GRK4 γ expressing the wild type variant (WT). Moreover, that AAV9-mediated renal specific overexpression of SLC4a5 in GRK4γ 65L mice increases the blood pressure (BP) response to a high salt diet compared with mice expressing empty vector (n=3; P&lt;0.05). We studied human renal proximal tubule cells (hRPTCs) endogenously expressing GRK4 WT and SLC4a5 WT, GRK4 65L, SLC4a5 variants and both GRK4 65L and SLC4a5 variants. SLC4A5 expression is increased in hRPTCs expressing GRK4 65L and in cells expressing both GRK4 65L and SLC4a5 variants (n=5, P&lt;0.05) compared with GRK4 WT. GRK4 can interact with nuclear histone deacetylases (HDACs) and co-immunoprecipitates with HDAC1 in nuclear fractions of hRPTCs. Renal-selective downregulation of HDAC1 increases BP in C57Bl/6J (P&lt;0.05) mice. hRPTCs carrying both GRK4 65L and SLC4a5 variants have decreased expression (60%; n=4; P&lt;0.05) of HDAC1 compared with cells expressing GRK4 WT and SLC4a5 WT or GRK4 65L This correlates with increased histone H4 acetylation but unchanged H2A, H2B and H3 acetylation in cells carrying both variants. Our results indicate a complex interaction between these variants in the regulation not only of SLC4a5 expression but that of other genes involved in salt sensitivity.